Neurotoxic.100101102 Neurotoxicity may be manifested by irritability, weakness, drowsiness, ataxia, perioral paresthesia, numbness of the extremities, and vision blurring.100101102 Usually associated with high polymyxin B serum concentrations found in patients with impaired renal function and/or nephrotoxicity.100101102

Neurotoxicity may result in respiratory paralysis from neuromuscular blockade, especially when given soon after anesthesia and/or muscle relaxants.100101102

Used intrathecally100101102136 or intraventricularly† for treatment of meningitis or other CNS infections.113136 May be effective when used intrathecally alone, but usually used in conjunction with a parenteral anti-infective (e.g., IV or IM polymyxin B, IV meropenem, IV penicillin, IV cephalosporin).113136

Penetrates poorly into CSF following IM or IV administration;100101102 do not use parenteral polymyxin B alone for treatment of meningitis or other CNS infections.146

Used for infections that are resistant to or do not respond to regimens of choice.100101102105136

Respiratory Tract Infections

Alternative for treatment of respiratory tract infections†, including nosocomial pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia, caused by multidrug-resistant gram-negative bacteria (e.g., Ps. aeruginosa,115122126Acinetobacter baumannii).115117122 Used in these infections only when other less toxic anti-infectives are ineffective or contraindicated.100101102105117121122

IV polymyxin B has been used alone or in conjunction with IV aztreonam for treatment of nosocomial pneumonia caused by multidrug-resistant Ps. aeruginosa, including those that produce metallo-β-lactamases.126 Nosocomial infections caused by metallo-β-lactamase-producing Ps. aeruginosa have a high mortality rate, and fatalities may occur despite appropriate anti-infective therapy.126 Optimal regimens for treatment of these infections not identified to date.126

Administered by oral inhalation via nebulization† for treatment of respiratory tract infections† caused by susceptible gram-negative bacteria (e.g., Ps. aeruginosa, A. baumannii).105109112116117122127 Generally used in conjunction with a parenteral anti-infective (e.g., IV polymyxin B);116117122 has been effective when given by oral inhalation alone in some patients with infections caused by susceptible gram-negative bacteria.116122

Although safety and efficacy not established and additional study needed, ATS, IDSA, and other clinicians suggest that adjunctive use of aerosolized polymyxin B can be considered for treatment of serious respiratory tract infections (e.g., ventilator-associated pneumonia) caused by multidrug-resistant gram-negative bacteria that have not responded to treatment with parenteral anti-infectives alone.107112116122

Septicemia

Treatment of septicemia or bacteremia caused by susceptible Ps. aeruginosa, Enterobacter aerogenes, or K. pneumoniae.100101102124 Also has been used for treatment of bloodstream infections caused by multidrug-resistant A. baumannii†.117

Generally used only when other less toxic anti-infectives are ineffective or contraindicated.100101102105121124

May be a drug of choice for treatment of septicemia or bacteremia caused by Ps. aeruginosa.100101102 Has been used alone or in conjunction with other anti-infectives (e.g., aztreonam) for infections caused by multidrug-resistant Ps. aeruginosa, including those that produce metallo-β-lactamases.124 Nosocomial blood stream infections caused by metallo-β-lactamase-producing Ps. aeruginosa have a high mortality rate, and fatalities may occur despite appropriate anti-infective therapy.124 Optimal regimens for treatment of these infections not identified to date.124

Urinary Tract Infections (UTIs)

Generally used only when other less toxic anti-infectives are ineffective or contraindicated.100101102105121

Bacteriuria and Bacteremia Associated with Indwelling Catheters

Fixed-combination solution for irrigation containing polymyxin B and neomycin used in abacteriuric patients for short-term (≤10 days) irrigation or rinse of the urinary bladder to help prevent bacteriuria and gram-negative rod septicemia associated with use of indwelling catheters.103104

Some clinicians state that irrigation or rinse of the urinary bladder with anti-infective solutions is unlikely to be of benefit while the catheter is in place and such a strategy is not recommended.146

Use fixed-combination solution for irrigation only for irrigation of the bladder; do not use for irrigation of other areas.103104

Polymyxin B Sulfate Dosage and Administration

Administration

Usually administered IV.100101102 May be given by IM injection, but IM administration not routinely recommended because severe pain occurs at injection site, especially in infants and children.100101102

Administer intrathecally100101102136 or intraventricularly† for treatment of meningitis or other CNS infections.113114136 Do not use IV or IM administration alone for treatment of meningitis or other CNS infections since distribution into CNS is expected to be low following these routes.100101102136

Although safety and efficacy not established, has been administered by oral inhalation via nebulization† for adjunctive treatment of respiratory tract infections†.105107112116117127

Fixed-combination solution for irrigation containing polymyxin B and neomycin is administered by continuous irrigation of the urinary bladder.103104

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Intrathecal Administration

Reconstitution

Reconstitute polymyxin B powder for injection by adding 10 mL of 0.9% sodium chloride injection to a vial containing 500,000 units to provide a solution containing approximately 50,000 units/mL.100101102 Do not use procaine hydrochloride solutions to prepare intrathecal injections.146a

Oral Inhalation

For oral inhalation via nebulization†, 0.5% solutions have been prepared using 0.9% sodium chloride.112 Polymyxin B concentrations >10 mg/mL should not be used for administration by oral inhalation since bronchial irritation may occur.105

Urinary Bladder Irrigation

Dilution

Add contents of a 1-mL ampul of the fixed-combination solution for irrigation containing 200,000 units of polymyxin B and 40 mg of neomycin to 1 L of 0.9% sodium chloride solution using strict aseptic technique.103104

Administer diluted solution for irrigation via a 3-way catheter at a rate of 1 L every 24 hours (approximately 40 mL/hour).103104 If patient's urine output is >2 L/day, the manufacturers recommend that inflow rate be adjusted to deliver 2 L every 24 hours.103104

If not used immediately, store diluted irrigation solution at 4°C and use within 48 hours.103104

Administer continuously for up to 10 days; do not interrupt the inflow or rinse solution for more than a few minutes.103104

Dosage

Available as polymyxin B sulfate; dosage expressed in terms of polymyxin B activity (units of polymyxin B)100101102105 or mg of polymyxin B base.100101102

Each mg of polymyxin B is equivalent to 10,000 units of polymyxin B.100101102105

Pediatric Patients

Meningitis and Other CNS Infections

Intrathecal

Infants <2 years of age: Initially, 20,000 units once daily for 3–4 days or 25,000 units once every other day.100101102 With either regimen, continue treatment with 25,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose is normal.100101102

Children ≥2 years: 50,000 units once daily for 3 to 4 days, followed by 50,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose is normal.100101102

Although safety and efficacy not established, a variety of other dosage regimens of intrathecal or intraventricular† polymyxin B (with or without concomitant parenteral therapy with IV or IM polymyxin B or other anti-infectives) have been used.136

Septicemia or Urinary Tract Bacterial Infections

IV

Infants with normal renal function: Up to 40,000 units/kg daily.100101102

IM

Infants with normal renal function: Up to 40,000 units/kg daily.100101102 Premature and full-term neonates have received up to 45,000 units/kg daily (4.5 mg/kg daily) for treatment of sepsis caused by Ps. aeruginosa in clinical studies.100101102

Daily dosage may be divided and given at 4- or 6-hour intervals.100101102

Adults

Meningitis and Other CNS Infections

Intrathecal

50,000 units once daily for 3–4 days, followed by 50,000 units once every other day given for at least 2 weeks after CSF cultures are negative and CSF glucose is normal.100101102

Although safety and efficacy not established, a variety of other dosage regimens of intrathecal or intraventricular† polymyxin B (with or without concomitant parenteral therapy with IV or IM polymyxin B or other anti-infectives) have been used.136

Adults have received 2.5 mg/kg daily in divided doses every 6 hours for adjunctive treatment of respiratory tract infections caused by susceptible Ps. aeruginosa.122127 If a 0.5% solution of the drug is prepared using 0.9% sodium chloride and this dosage regimen is used, the average 70-kg patient would receive 6 mL of solution per dose.112

Adults have received 500,000 units twice daily given approximately 20 minutes after an oral inhalation dose of a β2-adrenergic agonist.116

Oral inhalation has been used in conjunction with IV polymyxin B for treatment of pneumonia; oral inhalation has been used alone for treatment of tracheobronchitis caused by Ps. aeruginosa.116

Oral inhalation treatment has been continued for an average of 14 days (range: 4–25 days).116

Renal Impairment

Various dosage regimens have been recommended; these regimens are not well established and are not based on pharmacokinetic data from patients with renal impairment.105109115125134

It has been recommended that patients with Clcr 30–80 mL/minute receive an IV loading dose of 2.5 mg/kg on the first day of treatment followed by 1–1.5 mg/kg daily and that those with Clcr <25–30 mL/minute receive these doses once every 2–3 days.134 For anuric patients, some clinicians recommend an IV loading dose of 2.5 mg/kg followed by 1–1.5 mg/kg given once every 5–7 days.112134

Some clinicians suggest that patients with Clcr >20 mL/minute receive 75–100% of the usual daily dose in 2 divided doses every 12 hours, those with Clcr 5–20 mL/minute receive 50% of the usual daily dose in 2 divided doses every 12 hours, and those with Clcr <5 mL/minute receive 30% of the usual daily dose every 12–18 hours.105 Some have used 75% of the usual daily dose in those with Clcr 20–50 mL/minute and 33% of the usual daily dose in those with Clcr <20 mL/minute.115

Cautions for Polymyxin B Sulfate

Contraindications

Fixed combination solution for irrigation containing polymyxin B and neomycin solution: Hypersensitivity to polymyxins, neomycin, or any ingredient in the formulation.103104 History of hypersensitivity or serious toxic reaction to an aminoglycoside.103104

Warnings/Precautions

Warnings

Nephrotoxicity

Polymyxin B-associated nephrotoxicity is considered to be dose-dependent,111112 has been reported in 6–25% of patients receiving usual dosages,111112115117122 and generally is reversible after the drug is discontinued.112

Nephrotoxicity usually is manifested by albuminuria or proteinuria,100101102105111 cylindruria,100101102111 azotemia,100101102 increasing blood concentrations of the drug (not related to an increase in dosage),100101102 and an increase in serum creatinine concentration and decrease in Clcr.111 Acute tubular necrosis,111 oliguria,111 hematuria,105111 leukocyturia,a and excessive excretion of electrolytes may occur.a

Determine baseline renal function prior to initiation of polymyxin B therapy; monitor renal function frequently during therapy using blood tests and urinalysis.100101102146 The manufacturers also recommend that serum concentrations of the drug be monitored frequently during therapy.100101102 Use reduced dosage in patients with impaired renal function or renal damage and nitrogen retention.100101102 (See Renal Impairment under Dosage and Administration.)

Avoid concurrent or sequential use of other neurotoxic drugs.100101102111112 (See Interactions.)

Neuromuscular Blockade

Respiratory paralysis resulting in respiratory failure or apnea may occur as a result of neuromuscular blockade,100101102105111112 especially in patients with neuromuscular disease such as myasthenia gravis or in patients who are receiving neuromuscular blocking agents or general anesthetics.100101102111112 (See Interactions.)

Polymyxin B-induced neuromuscular blockade is not easily reversed and is resistant to neostigmine105 and edrophonium;a calcium chloride has been used successfully in some cases.105

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of polymyxin B and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.100101102

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.100101102 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.100101102

Superinfection

As with other anti-infectives, use of polymyxin B may result in overgrowth of nonsusceptible organisms, including fungi.100101102 Institute appropriate therapy if superinfection occurs.100101102

Consider the precautions and contraindications related to both polymyxin B and neomycin.103104

Should be used only for irrigation of the bladder; do not use for irrigation of other areas.103104

Do not use for prophylactic bladder care if there is a possibility of systemic absorption.103104 The likelihood of toxicity following topical irrigation of the intact urinary bladder is low since appreciable amounts of polymyxin B or neomycin do not enter systemic circulation if the duration of irrigation is ≤10 days.103104 However, absorption of neomycin from the denuded bladder surface has been reported.103104 Systemic absorption after topical application of neomycin to open wounds, burns, and granulating surfaces is clinically significant, and serum concentrations comparable to or higher than those attained following oral and parenteral therapy have been reported.103104

Use only for continuous prophylactic irrigation (maximum of 10 days) of the lumen of the intact urinary bladder of patients with indwelling catheters who are under constant supervision by a clinician.103104 Because of the risk of toxicity due to systemic absorption following diffusion into absorptive tissues and spaces, avoid use if there are defects in bladder mucosa or bladder wall, such as vesical rupture, or in association with operative procedures on the bladder wall.103104

If absorption occurs, consider that both polymyxin B and neomycin are nephrotoxic and neurotoxic and that the effects of the drugs may be additive.103104

Specific Populations

Pregnancy

Some clinicians state that polymyxin B should not be used during pregnancy, except in rare situations when other appropriate anti-infectives cannot be used.146

Fixed-combination solution for irrigation containing polymyxin B and neomycin: If use is being considered for a pregnant woman, inform the woman of the potential hazard to the fetus.103104 Aminoglycosides cross the placenta and there have been reports of complete, irreversible, bilateral congenital deafness in children whose mothers received an aminoglycoside (i.e., streptomycin) during pregnancy.103104

Pediatric Use

Polymyxin B: Used IV in infants and children.100101102 IM route not routinely used in infants and children because severe pain occurs at the injection site, especially in this age group.100101102

Fixed-combination solution for irrigation containing polymyxin B and neomycin: Safety and efficacy not established in children.103104

Renal Impairment

Risk of nephrotoxicity and neurotoxicity may be increased in patients with renal impairment;105112 use reduced dosage.14100101102105112125 (See Renal Impairment under Dosage and Administration.)

Interactions for Polymyxin B Sulfate

Nephrotoxic and Neurotoxic Drugs

Since nephrotoxic and neurotoxic effects may be additive, concurrent or sequential use of polymyxin B and other nephrotoxic and/or neurotoxic drugs, particularly bacitracin, aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin), colistimethate/colistin, and viomycin (not commercially available in the US) should be avoided.100101102111112145

In vitro evidence of synergistic antibacterial effects between polymyxin B and azithromycin against some strains of multidrug-resistant Ps. aeruginosa; the combination has been bactericidal against some strains, but bacteriostatic against other strains143

Clinical importance of in vitro studies evaluating combination of polymyxin B and azithromycin against gram-negative bacteria is unclear143

Carbapenems (imipenem, meropenem)

In vitro evidence of synergistic antibacterial effects between polymyxin B and imipenem against Ps. aeruginosa;143 indifferent antibacterial effects in vitro when combined with meropenem142

Conflicting in vitro results reported with imipenem or meropenem against A. baumannii;118119125133142143 in vitro antibacterial effects have been synergistic, partially synergistic, additive, or indifferent118125133142

Clinical importance of in vitro studies evaluating combinations of polymyxin B and carbapenems against gram-negative bacteria is unclear119143

In vitro evidence of synergistic antibacterial effects between polymyxin B and rifampin against multidrug-resistant Ps. aeruginosa; a 3-drug combination of polymyxin B, rifampin, and imipenem was more consistently bactericidal against these strains143

In some in vitro studies, combination of polymyxin B and rifampin (with or without imipenem) was synergistic or additive against A. baumannii118125133

Combination of polymyxin B and rifampin was synergistic in vitro against K. pneumoniae125

Clinical importance of in vitro studies evaluating combinations of polymyxin B and rifampin against gram-negative bacteria is unclear143

Polymyxin B Sulfate Pharmacokinetics

Absorption

Bioavailability

Not absorbed to an appreciable extent from mucous membranes14 or intact or denuded skin.14a

After IM administration of a single dose of 20,000–40,000 units/kg (2–4 mg/kg) in adults, peak serum concentrations of 1–8 mcg/mL are obtained144 within approximately 2 hours.a Drug may be detectable in serum for up to 12 hours.a

Serum concentrations are higher in infants and children than in adults.100101102

In critically ill adults who received doses of 0.5–1.5 mg/kg by IV infusion over 60 minutes, peak plasma concentrations at completion of the infusion ranged from 2.38–13.9 mcg/mL and concentrations of polymyxin B1 were fourfold higher than concentrations of polymyxin B2.123 (See Actions.)

Special Populations

Serum concentrations are higher and more prolonged in patients with renal impairment.105 (See Actions.)

Distribution

Extent

Diffuses poorly in tissues.100101102 Does not distribute into synovial fluid or aqueous humor following systemic administration.a

Following IV or IM administration, not distributed into CSF100101102105 (even when meninges are inflamed).a

Plasma Protein Binding

In an in vitro study using plasma from critically ill adults, polymyxin B was 78.5–92.4% bound to plasma proteins; however, mean protein binding was only 55.9% when testing was done using pooled plasma from healthy individuals.123

Elimination

Elimination Route

Eliminated in urine principally by glomerular filtration.144 Some studies indicate only low amounts of the dose eliminated in urine within the first 12 hours after a dose, but eventually approximately 60% of a dose excreted in urine.105 Other studies suggest that <1% of a dose eliminated unchanged in urine over 3 days.123

Acts like a cationic detergent and binds to and damages bacterial cytoplasmic membrane of susceptible bacteria causing alteration of the osmotic barrier and leakage of essential intracellular components.14105112125144

Two types of resistance to polymyxin B have been identified in Ps. aeruginosa, including low-level, transmissible mutations and high-level, stepwise resistance.140

Complete cross-resistance occurs between polymyxin B and colistin; cross-resistance with other anti-infectives not reported to date.105125131140144

Advice to Patients

Advise patients that antibacterials (including polymyxin B) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).100101102

Importance of completing full course of therapy, even if feeling better after a few days.100101102

Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with polymyxin B or other antibacterials in the future.100101102

Importance of informing clinicians of existing concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., renal impairment, neuromuscular disease).100101102

Importance of women informing their clinician if they are or plan to become pregnant.100101102

Importance of informing patients of other important precautionary information.100101102 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

127. Falagas ME, Kasiakou SK. Local administration of polymyxins into the respiratory tract for the prevention and treatment of pulmonary infections in patients without cystic fibrosis. Infection. 2007; 35:3-10. http://www.ncbi.nlm.nih.gov/pubmed/17297582?dopt=AbstractPlus